US20020183308A1 - Benazepril Hydrochloride tablet formulations - Google Patents
Benazepril Hydrochloride tablet formulations Download PDFInfo
- Publication number
- US20020183308A1 US20020183308A1 US10/120,388 US12038802A US2002183308A1 US 20020183308 A1 US20020183308 A1 US 20020183308A1 US 12038802 A US12038802 A US 12038802A US 2002183308 A1 US2002183308 A1 US 2002183308A1
- Authority
- US
- United States
- Prior art keywords
- tablets
- lubricant
- benazepril hydrochloride
- tablet
- magnesium stearate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VPSRQEHTHIMDQM-FKLPMGAJSA-N benazepril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 VPSRQEHTHIMDQM-FKLPMGAJSA-N 0.000 title claims abstract description 18
- 229960003619 benazepril hydrochloride Drugs 0.000 title claims abstract description 18
- 239000007916 tablet composition Substances 0.000 title description 2
- 239000000314 lubricant Substances 0.000 claims abstract description 21
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 26
- 235000019359 magnesium stearate Nutrition 0.000 description 13
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 239000004359 castor oil Substances 0.000 description 5
- 235000019438 castor oil Nutrition 0.000 description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- -1 for example Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940080268 lotensin Drugs 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- Benazepril hydrochloride is a medicinal compound useful as an antihypertensive agent. Its ability to inhibit the angiotension converting enzyme and thus lower blood pressure is disclosed in U.S. Pat. No. 4,410,520.
- Tablets comprising benazepril hydrochloride are sold in the United States and elsewhere under the tradename LotensinTM. These tablets comprise, in addition to benazepril hydrochloride as active ingredient, various inactive ingredients, which include a lubricant to avoid sticking to the punches in the tabletting process.
- the lubricant used in the 5 mg and 10 mg tablets is hydrogenated castor oil, while that used in the 40 mg tablets is magnesium stearate.
- Magnesium stearate is the most commonly used lubricant in pharmaceutical tablets. However, it accelerates the rate of degradation of benazepril hydrochloride, so that benazepril hydrochloride tablets which comprise magnesium stearate have a shorter shelf life than would be the case without magnesium stearate.
- LotensinTM 5 mg and 10 mg tablets are made using hydrogenated castor oil instead of magnesium stearate as a lubricant in order to achieve a lower degradation rate. It further appears that 40 mg tablets could not be made using hydrogenated castor oil as the only lubricant (i.e. without magnesium stearate) because hydrogenated castor oil is relatively ineffective as a lubricant, and is not sufficiently effective to eliminate sticking in the higher strength (40 mg) tablets.
- the object of the present invention is thus to provide a lubricant for benazepril hydrochloride tablets that is more effective than hydrogenated castor oil as a lubricant, but does not cause degradation of the benazepril hydrochloride to the same extent as does magnesium stearate.
- the invention is thus a pharmaceutical tablet comprising benazepril hydrochloride and zinc stearate as the lubricant.
- the tablet formulation will also comprise at least one other excipient as a filler and binder, such as, for example, microcrystalline cellulose or lactose.
- a filler and binder such as, for example, microcrystalline cellulose or lactose.
- the preferred filler is microcrystalline cellulose.
- the tablet will also optionally comprise a disintegrant, such as, for example, starch, croscarmellose sodium, sodium starch glycolate, or crospovidone.
- a disintegrant such as starch, croscarmellose sodium, sodium starch glycolate, or crospovidone.
- the preferred disintegrant is crospovidone.
- the tablet will also optionally comprise other excipients, such as colloidal silicon dioxide as glidant, or a colour agent.
- the tablets will also optionally contain another active ingredient, such as a diuretic.
- the quantity of the lubricant as a percentage of the total tablet weight will preferably be from about 0.2 percent to about 3.0 percent.
- the benazepril hydrochloride tablets of this invention can be prepared by conventional tablet forming techniques such as, for example, wet granulation and dry granulation.
- wet granulation the active ingredient or ingredients are mixed with some or all of the filler.
- This blend is then wet granulated with a solution of a binder in solvent.
- the resultant wet mass is then dried and milled.
- the granules are then mixed with the remaining ingredients, which will include the lubricant, to produce the final mix, which is then compressed into tablets.
- the active ingredient or ingredients are mixed with the other ingredients without addition of any solvent, and thus without the need for drying. Again the final mix is compressed into tablets.
- the dry granulation approach is preferred, as it is simpler and thus less costly.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
Stable tablets comprising benazepril hydrochloride are prepared by employing zinc stearate as the lubricant.
Description
- Benazepril hydrochloride is a medicinal compound useful as an antihypertensive agent. Its ability to inhibit the angiotension converting enzyme and thus lower blood pressure is disclosed in U.S. Pat. No. 4,410,520.
- Tablets comprising benazepril hydrochloride are sold in the United States and elsewhere under the tradename Lotensin™. These tablets comprise, in addition to benazepril hydrochloride as active ingredient, various inactive ingredients, which include a lubricant to avoid sticking to the punches in the tabletting process.
- According to the literature for Lotensin™, the lubricant used in the 5 mg and 10 mg tablets is hydrogenated castor oil, while that used in the 40 mg tablets is magnesium stearate. Magnesium stearate is the most commonly used lubricant in pharmaceutical tablets. However, it accelerates the rate of degradation of benazepril hydrochloride, so that benazepril hydrochloride tablets which comprise magnesium stearate have a shorter shelf life than would be the case without magnesium stearate.
- It appears that Lotensin™ 5 mg and 10 mg tablets are made using hydrogenated castor oil instead of magnesium stearate as a lubricant in order to achieve a lower degradation rate. It further appears that 40 mg tablets could not be made using hydrogenated castor oil as the only lubricant (i.e. without magnesium stearate) because hydrogenated castor oil is relatively ineffective as a lubricant, and is not sufficiently effective to eliminate sticking in the higher strength (40 mg) tablets.
- The 40 mg strength of Lotensin™ tablets thus has a relatively high degradation rate.
- The object of the present invention is thus to provide a lubricant for benazepril hydrochloride tablets that is more effective than hydrogenated castor oil as a lubricant, but does not cause degradation of the benazepril hydrochloride to the same extent as does magnesium stearate.
- It has been found that zinc stearate is an effective lubricant for benazepril hydrochloride tablets.
- Moreover, it has been surprisingly found that the rate of degradation of benazepril hydrochloride in tablets comprising zinc stearate as lubricant is much lower than in tablets comprising magnesium stearate as lubricant.
- The invention is thus a pharmaceutical tablet comprising benazepril hydrochloride and zinc stearate as the lubricant.
- In addition to benazepril hydrochloride as the active ingredient, and zinc stearate as the lubricant, the tablet formulation will also comprise at least one other excipient as a filler and binder, such as, for example, microcrystalline cellulose or lactose. The preferred filler is microcrystalline cellulose.
- The tablet will also optionally comprise a disintegrant, such as, for example, starch, croscarmellose sodium, sodium starch glycolate, or crospovidone. The preferred disintegrant is crospovidone. The tablet will also optionally comprise other excipients, such as colloidal silicon dioxide as glidant, or a colour agent. The tablets will also optionally contain another active ingredient, such as a diuretic.
- The quantity of the lubricant as a percentage of the total tablet weight will preferably be from about 0.2 percent to about 3.0 percent.
- The benazepril hydrochloride tablets of this invention can be prepared by conventional tablet forming techniques such as, for example, wet granulation and dry granulation. In the wet granulation process, the active ingredient or ingredients are mixed with some or all of the filler. This blend is then wet granulated with a solution of a binder in solvent. The resultant wet mass is then dried and milled. The granules are then mixed with the remaining ingredients, which will include the lubricant, to produce the final mix, which is then compressed into tablets.
- In the dry granulation process, the active ingredient or ingredients are mixed with the other ingredients without addition of any solvent, and thus without the need for drying. Again the final mix is compressed into tablets. The dry granulation approach is preferred, as it is simpler and thus less costly.
- The invention will be further understood from the following examples:
Example No: 1 2 Benazepril Hydrochloride 40.0 40.0 Microcrystalline Cellulose 58.7 57.2 Crospovidone 0.5 2.0 Colloidal Silicon Dioxide 0.2 0.2 Magnesium Stearate 0.6 X Zinc Stearate X 0.6 100.0 100.0 - For each of the 2 examples, the ingredients in the proportions listed were mixed together. The powder mixture was then passed through a #60 screen and mixed again. The powder mixture was then compressed into tablets of weight 100 mg each, so that each tablet contained 40 mg of benazepril hydrochloride.
- Tablets of each of the examples as well as Lotensin™ tablets 40 mg were stored at 60° C. for two weeks and then tested by an HPLC method to determine the degradation products as a percentage of the initial benazepril hydrochloride content.
- The results were as follows:
Example No. Lubricant % Degradation Products 1 Magnesium Stearate 1.24% 2 Zinc Stearate 0.57% Lotensin ™ 40 mg Magnesium Stearate 1.68% - It can be seen that the percentage degradation is much lower for the tablets of example 2 (which comprise zinc stearate as lubricant) than for either the tablets of example 1 or Lotensin™ 40 mg tablets, both of which comprise magnesium stearate.
- It is thus found that, while degradation rate is relatively high when magnesium stearate is used as lubricant, the degradation rate is much lower when zinc stearate is used as lubricant.
Claims (4)
1. A pharmaceutical tablet comprising benazepril hydrochloride and zinc stearate.
2. A tablet as in claim 1 further comprising microcrystalline cellulose.
3. A tablet as in claim 2 further comprising crospovidone.
4. A tablet as in any of claims 1 to 3 where the amount of lubricant by weight is from about 0.2 percent to about 3 percent of the total tablet weight.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002343949A CA2343949A1 (en) | 2001-04-12 | 2001-04-12 | Benazepril hydrochloride tablet formulations |
| CA2,343,949 | 2001-04-12 | ||
| CA2343949 | 2001-04-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20020183308A1 true US20020183308A1 (en) | 2002-12-05 |
| US6737419B2 US6737419B2 (en) | 2004-05-18 |
Family
ID=4168818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/120,388 Expired - Fee Related US6737419B2 (en) | 2001-04-12 | 2002-04-12 | Benazepril hydrochloride tablet formulations |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US6737419B2 (en) |
| CA (1) | CA2343949A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006092732A3 (en) * | 2005-03-04 | 2007-03-29 | Aurobindo Pharma Ltd | Stable solid dosage form of antihypertensive agent |
| EP1930008A1 (en) * | 2005-09-28 | 2008-06-11 | Teva Pharmaceutical Industries Ltd | Sable composition of benazepril hydrochloride |
| US8158146B2 (en) | 2005-09-28 | 2012-04-17 | Teva Pharmaceutical Industries Ltd. | Stable combinations of amlodipine besylate and benazepril hydrochloride |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2363053C (en) * | 2001-11-09 | 2011-01-25 | Bernard Charles Sherman | Clopidogrel bisulfate tablet formulation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4410520A (en) * | 1981-11-09 | 1983-10-18 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| US6372255B1 (en) * | 1997-12-23 | 2002-04-16 | Merck Patent Gesellschaft | Tablet for instant and prolonged release of one or more active substances |
| US6652882B1 (en) * | 1997-10-06 | 2003-11-25 | Intellipharmaceutics Corp | Controlled release formulation containing bupropion |
-
2001
- 2001-04-12 CA CA002343949A patent/CA2343949A1/en not_active Abandoned
-
2002
- 2002-04-12 US US10/120,388 patent/US6737419B2/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4410520A (en) * | 1981-11-09 | 1983-10-18 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| US6652882B1 (en) * | 1997-10-06 | 2003-11-25 | Intellipharmaceutics Corp | Controlled release formulation containing bupropion |
| US6372255B1 (en) * | 1997-12-23 | 2002-04-16 | Merck Patent Gesellschaft | Tablet for instant and prolonged release of one or more active substances |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006092732A3 (en) * | 2005-03-04 | 2007-03-29 | Aurobindo Pharma Ltd | Stable solid dosage form of antihypertensive agent |
| EP1930008A1 (en) * | 2005-09-28 | 2008-06-11 | Teva Pharmaceutical Industries Ltd | Sable composition of benazepril hydrochloride |
| US8158146B2 (en) | 2005-09-28 | 2012-04-17 | Teva Pharmaceutical Industries Ltd. | Stable combinations of amlodipine besylate and benazepril hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| US6737419B2 (en) | 2004-05-18 |
| CA2343949A1 (en) | 2002-10-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20120518 |